Clinical presentation of bacille Calmette-Guérin (BCG) infections after BCG instillation therapy.

OBJECTIVES: To investigate the timing of the clinical presentation of various types of bacille Calmette-Guérin (BCG) infections in a Finnish population of patients with bladder cancer treated with BCG instillation therapy. PATIENTS AND METHODS: We identified patients with a history of post-instillation BCG infection from 1996 to 2016 using the Finnish Cancer Registry and the Finnish National Infectious Diseases Registry. We categorised infections as systemic if the infection was found in the non-urogenital system and genitourinary (GU) if the infection affected the urogenital tract. We calculated the time interval between the last BCG instillation and the presentation of the infection. The infection was considered late if the time interval was ≥1 year. RESULTS: A total of 100 patients with BCG infection were identified during the study period. In all, 39 (39%) infections presented as systemic and 61 (61%) were in the GU tract. The majority of the systemic infections presented rapidly after the last instillation, while five (13%) presented after a latency of ≥1 year. The presentation of GU infections was more heterogeneous, with 12 (20%) presenting as late infections. CONCLUSION: This study confirms the concept of early and late infection types, especially among systemic infections. However, late infections appeared to be rarer than previously described. Urologists should be aware of the possibility of late BCG infection if patients develop symptoms even several years after the BCG regimen.

Incidence of and mortality from Bacille Calmette-Guérin (BCG) infections after BCG instillation therapy.

OBJECTIVES: To investigate the incidence of and mortality associated with Bacille Calmette-Guérin (BCG) infections in a Finnish population of patients with bladder cancer treated with BCG instillations. MATERIALS AND METHODS: We conducted a nationwide register study and identified patients with BCG infections in Finland during 1996 to 2016 using the Finnish Cancer Registry and the Finnish National Infectious Diseases Register. We estimated the number of patients treated with BCG instillations based on data on national consumed BCG doses used to treat patients with bladder cancer, and calculated the annual incidence proportion of BCG infections. We further performed a detailed medical chart review to describe the clinical features and outcomes of the treated BCG infections. RESULTS: In total, 87 patients with BCG infection after BCG treatment of bladder cancer were identified. The incidence proportion increased gradually, yielding a cumulative incidence proportion of 2.5% during the latter half of the study period. BCG infections led to significant mortality, with 10% overall mortality and 17.5% mortality from systemic infections, which is notably higher than previously reported. CONCLUSION: The incidence proportion of BCG infections among bladder cancer patients treated with BCG has increased in Finland up to 2.5% at a nationwide level, with a notably higher mortality rate than previously reported.

Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.

Fecal transplantation, through colonoscopy, is effective therapy for recurrent Clostridium difficile infection.

BACKGROUND & AIMS: Treatment of recurrent Clostridium difficile infection (CDI) with antibiotics leads to recurrences in up to 50% of patients. We investigated the efficacy of fecal transplantation in treatment of recurrent CDI. METHODS: We reviewed records from 70 patients with recurrent CDI who had undergone fecal transplantation. Fecal transplantation was performed at colonoscopy by infusing fresh donor feces into cecum. Before transplantation, the patients had whole-bowel lavage with polyethylene glycol solution. Clinical failure was defined as persistent or recurrent symptoms and signs, and a need for new therapy. RESULTS: During the first 12 weeks after fecal transplantation, symptoms resolved in all patients who did not have strain 027 C difficile infections. Of 36 patients with 027 C difficile infection, 32 (89%) had a favorable response; all 4 nonresponders had a pre-existing serious condition, caused by a long-lasting diarrheal disease or comorbidity and subsequently died of colitis. During the first year after transplantation, 4 patients with an initial favorable response had a relapse after receiving antibiotics for unrelated causes; 2 were treated successfully with another fecal transplantation and 2 with antibiotics for CDI. Ten patients died of unrelated illnesses within 1 year after transplantation. No immediate complications of fecal transplantation were observed. CONCLUSIONS: Fecal transplantation through colonoscopy seems to be an effective treatment for recurrent CDI and also for recurrent CDI caused by the virulent C difficile 027 strain.

Role of plasma bactericidal/permeability-increasing protein, group IIA phospholipase A(2), C-reactive protein, and white blood cell count in the early detection of severe sepsis in the emergency department.

OBJECTIVES: To study the diagnostic values of bactericidal/permeability-increasing protein (BPI), group IIA phospholipase A(2) (PLA(2)GIIA), white blood cell count (WBC), and C-reactive protein (CRP) in identifying severe sepsis upon admission in an emergency room. METHODS: This was a single-centre prospective cohort study involving 525 adult patients admitted to the emergency room with suspected infection. Plasma samples were taken concurrently with the blood cultures. Forty-nine patients with severe sepsis and 476 other patients (58 with no systemic inflammatory response syndrome (SIRS) and no bacterial infection, 63 with bacterial infection but no SIRS, 53 with SIRS but no bacterial infection, and 302 with sepsis but no organ dysfunction) were evaluated. BPI and PLA(2)GIIA were measured by time-resolved fluoroimmunoassay, and CRP with an immunoturbidimetric assay. WBC was measured using an automatic cell counter. RESULTS: There was a positive correlation between the plasma levels of PLA(2)GIIA and CRP (Pearson's correlation coefficient 0.60, p < 0.001). On logistic regression analysis the odds ratio (OR) (95% confidence limits (95% Cl)) for BPI was 2.66 (1.54-4.60, p = 0.001), for PLA(2)GIIA 1.48 (1.20-1.81, p < 0.001), for CRP 1.35 (1.02-1.77, p = 0.036), and for WBC 2.81 (1.48-5.34, p = 0.002). The differences in area under the receiver operator characteristic curve (AUC) between these parameters were not significant. On multivariate logistic regression analysis only PLA(2)GIIA could differentiate patients with severe sepsis from others (OR 1.37, 95% Cl 1.05-1.78, p = 0.019). After adjusting for confounders PLA(2)GIIA remained a significant independent predictor of severe sepsis. CONCLUSIONS: PLA(2)GIIA seemed to be superior to CRP, BPI, and WBC in differentiating patients with severe sepsis. BPI gave no additional information in this respect.

Early detection of severe sepsis in the emergency room: diagnostic value of plasma C-reactive protein, procalcitonin, and interleukin-6.

OBJECTIVES: To determine the diagnostic values of plasma C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) using an electrochemiluminescence immunoassay (ECLIA) method (Roche Diagnostics GmbH, Mannheim, Germany) to identify severe sepsis in an emergency room (ER) setting. METHODS: This was a single-centre prospective follow-up study of 539 consecutive adult patients admitted to the ER with suspected infection. Blood samples were taken concurrently with blood cultures at admission. Patients were divided into 5 groups on the basis of systemic inflammatory response syndrome (SIRS) criteria, documentation of bacterial infection, and organ dysfunction. Fifty-nine patients with no SIRS or bacterial infection, 68 patients with bacterial infection but no SIRS, 54 patients with SIRS but no bacterial infection, 309 patients with sepsis (SIRS and bacterial infection), and 49 patients with severe sepsis (sepsis and organ failure) were evaluated. RESULTS: In a logistic regression model, the odds ratio (OR) for PCT was 1.58 (95% confidence interval (CI) 1.37-1.82, p < 0.0001), for IL-6 was 1.54 (95% CI 1.32-1.80, p < 0.0001), and for CRP was 1.33 (95% CI 1.01-1.75, p = 0.045). The area under the curve (AUC) was 0.77 (95% CI 0.71-0.84) for PCT, 0.72 (95% CI 0.64-0.80) for IL-6, and 0.60 (95% CI 0.51-0.69) for CRP. PCT emerged as the best marker for severe sepsis, but the difference in AUC was not significant between PCT and IL-6. In multivariate logistic regression analysis, after adjusting for confounders, PCT and IL-6 remained significant independent predictors of severe sepsis. CONCLUSIONS: PCT and IL-6 proved superior to CRP in detecting patients with severe sepsis. The findings thus support the use of either PCT or IL-6 as an early tool to diagnose severe sepsis. The automatic ECLIA method allows even night-shift measurements.

Routine Treatment-Resistant Clostridium difficile Infection during Recovery from Myxedema.

Development of the extreme form of hypothyroidism defined as myxedema is very rare. Acute symptoms and their management have been described in detail previously. However, not much attention has been devoted to therapeutic challenges that are faced in the recovery phase of the treatment, especially pertaining to the gastrointestinal system. The link between myxedema and the appearance of severe Clostridium difficile infection (CDI) has not been established so far. A 61-year-old woman with no significant medical record was admitted to hospital because of infected heel pressure and thyroid dysfunction. A week later, due to hypothermia, hypotension, and unconsciousness, she was transferred to the intensive care unit. The clinical picture and the results of laboratory tests confirmed diagnosis of myxedema. After the introduction of resuscitative measures and hormonal substitution, patient's condition stabilized within 10 days. Due to concomitant sepsis, initially piperacillin/tazobactam and later cefuroxime were administered. After 20 days of antibiotic therapy, the patient developed CDI that was resistant to the routine mode of treatment. The clinical recovery was achieved only after a fecal microbiota transplantation procedure. The function of the digestive tract in myxedema is disturbed by gastric achlorydia and reduced peristalsis, which in turn can predispose the small intestine to overgrowth of bacteria. The use of antibiotics can additionally decrease the intestinal bacterial diversity, favoring the overgrowth of Clostridium difficile. The authors conclude that myxedema may increase the likelihood of a treatment-resistant form of CDI that requires the implementation of fecal microbiota transplantation.

Pentraxin 3 (PTX3) is associated with severe sepsis and fatal disease in emergency room patients with suspected infection: a prospective cohort study.

BACKGROUND: Early diagnostic and prognostic stratification of patients with suspected infection is a difficult clinical challenge. We studied plasma pentraxin 3 (PTX3) upon admission to the emergency department in patients with suspected infection. METHODS: The study comprised 537 emergency room patients with suspected infection: 59 with no systemic inflammatory response syndrome (SIRS) and without bacterial infection (group 1), 67 with bacterial infection without SIRS (group 2), 54 with SIRS without bacterial infection (group 3), 308 with sepsis (SIRS and bacterial infection) without organ failure (group 4) and 49 with severe sepsis (group 5). Plasma PTX3 was measured on admission using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: The median PTX3 levels in groups 1-5 were 2.6 ng/ml, 4.4 ng/ml, 5.0 ng/ml, 6.1 ng/ml and 16.7 ng/ml, respectively (p<0.001). The median PTX3 concentration was higher in severe sepsis patients compared to others (16.7 vs. 4.9 ng/ml, p<0.001) and in non-survivors (day 28 case fatality) compared to survivors (14.1 vs. 5.1 ng/ml, p<0.001). A high PTX3 level predicted the need for ICU stay (p<0.001) and hypotension (p<0.001). AUC(ROC) in the prediction of severe sepsis was 0.73 (95% CI 0.66-0.81, p<0.001) and 0.69 in case fatality (95% CI 0.58-0.79, p<0.001). PTX3 at a cut-off level for 14.1 ng/ml (optimal cut-off value for severe sepsis) showed 63% sensitivity and 80% specificity. At a cut-off level 7.7 ng/ml (optimal cut-off value for case fatality) showed 70% sensitivity and 63% specificity in predicting case fatality on day 28.In multivariate models, high PTX3 remained an independent predictor of severe sepsis and case fatality after adjusting for potential confounders. CONCLUSIONS: A high PTX3 level on hospital admission predicts severe sepsis and case fatality in patients with suspected infection.